This proposal presents a multidisciplinary approach to understanding a fundamental property of sensory processing: the modulation of sensory perception by acetylcholine. The proposal addresses this question in the olfactory bulb of rats, using a combination of computational modeling, brain slice physiology, in vivo electrophysiology and behavioral pharmacology. The mammalian olfactory system offers several unique advantages for such studies. First, the olfactory system is anatomically relatively simple and this simplicity has resulted in an extensive knowledge of its synaptic connections and physiology. Second, because olfactory bulb principal neurons are a single synapse removed from sensory neurons, a relatively clear relationship between neural representations in the bulb and the perceptual properties of olfactory signals has been established. Third, this knowledge in turn has enabled the development of computational models crucial for the interpretation and integration of experimental data. A collaborative effort between three labs will investigate the interplay between muscarinic and nicotinic receptor activation and the functional consequences of their coordinated activation. Specifically, we will (1) determine the effects of muscarinic and nicotinic receptor activation on olfactory bulb neural circuits in a detailed biophysical model, (2) test the cellular and synaptic effects of such modulation using brain slice electrophysiology, (3) use in vivo electrophysiology to determine the effect of cholinergic modulation on odor responses, and (4) test the functional predictions arising from these experiments in behavioral pharmacology experiments. Taken together, the proposed simulations and experiments will elucidate how nicotinic and muscarinic receptors interact within a coordinated neural circuit to improve contrast and signal-to-noise properties in early olfactory processing.